Ibrutinib inhibits pre-BCR+ B-cell acute lymphoblastic leukemia progression by targeting BTK and BLK
Ibrutinib inhibits pre-BCR+ B-cell acute lymphoblastic leukemia progression by targeting BTK and BLK
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DOI：
10.1182/blood-2016-06-722900
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发表时间：
2017-03-02
期刊：
影响因子：
20.3
通讯作者：
Burger, Jan A.
中科院分区：
文献类型：
--
作者：
Kim, Ekaterina;Hurtz, Christian;Burger, Jan A.
靶向 B 细胞受体 (BCR) 信号传导是成熟 B 细胞恶性肿瘤的成功治疗策略。前体 BCR (pre-BCR) 信号在正常 B 淋巴细胞生成过程中至关重要，在前 BCR+ B 细胞急性淋巴细胞白血病 (B-ALL) 中也发挥着重要作用。在这里，我们研究了 BTK 抑制剂依鲁替尼在 B-ALL 临床前模型中的活性和作用机制。 Pre-BCR+ ALL 细胞对治疗相关药物浓度的依鲁替尼极其敏感。在前 BCR+ ALL 中，依鲁替尼阻碍自主并诱导前 BCR 信号传导，导致 PI3K/Akt 信号传导失活。依鲁替尼调节前 BCR 调节因子（PTPN6、CD22、CD72 和 PKC beta）的表达并显着降低 BCL6 水平。依鲁替尼抑制 ALL 细胞向 CXCL12 和骨髓基质细胞下方迁移，并减少 CD44 表达。 CRISPR-Cas9 基因编辑显示，BTK 和 B 淋巴细胞激酶 (BLK) 都是依鲁替尼治疗 BCR+ 前 ALL 的相关靶点。因此，在 BCR+ ALL 前的小鼠异种移植模型中，依鲁替尼治疗显着延长了生存期。依鲁替尼与地塞米松或长春新碱的联合治疗显示出针对 BCR+ ALL 之前的协同活性。这些数据证实了依鲁替尼作为治疗 BCR+ 前 ALL 的有前途的靶向药物，并强调了依鲁替尼对替代激酶靶点作用的重要性。 （血。2017；129（9）：1155-1165）
Targeting B-cell receptor (BCR) signaling is a successful therapeutic strategy in mature B-cell malignancies. Precursor BCR (pre-BCR) signaling, which is critical during normal B lymphopoiesis, also plays an important role in pre-BCR+ B cell acute lymphoblastic leukemia (B-ALL). Here, we investigated the activity and mechanism of action of the BTK inhibitor ibrutinib in preclinical models of B-ALL. Pre-BCR+ ALL cells were exquisitely sensitive to ibrutinib at therapeutically relevant drug concentrations. In pre-BCR+ ALL, ibrutinib thwarted autonomous and induced pre-BCR signaling, resulting in deactivation of PI3K/Akt signaling. Ibrutinib modulated the expression of pre-BCR regulators (PTPN6, CD22, CD72, and PKC beta) and substantially reduced BCL6 levels. Ibrutinib inhibited ALL cell migration toward CXCL12 and beneath marrow stromal cells and reduced CD44 expression. CRISPR-Cas9 gene editing revealed that both BTK and B lymphocyte kinase (BLK) are relevant targets of ibrutinib in pre-BCR+ ALL. Consequently, in mouse xenograft models of pre-BCR+ ALL, ibrutinib treatment significantly prolonged survival. Combination treatment of ibrutinib with dexamethasone or vincristine demonstrated synergistic activity against pre-BCR+ ALL. These data corroborate ibrutinib as a promising targeted agent for pre-BCR+ ALL and highlight the importance of ibrutinib effects on alternative kinase targets. (Blood. 2017; 129(9): 1155-1165)